The proposed research is concerned with metabolic alterations in the brain which occur in exerimentally-induced amino acid imbalances. Comprehensive studies will be carried out on the effect of acute and chronic hyperaminoacidemias on processes which may be involved in the regulation of amino acid and protein metabolism in the brain. The amino ocids given in excess will include phenylalanine, leucine, histidine and lysine. These amino acids have markedly diverse metabolic properties, but are all involved in aminoacidopathies which are associated with overt brain damage in human infants. The specific points to be investigated are: (a) developmental and regional differences in the sensitivity of the brain to alterations in amino acid distribution and metabolism resulting from acute or chronic parenteral administration of an amino acid load, (b) the relationship of the resulting amino acid imbalance to possible variations in the synthesis of brain proteins and (c) the basic metabolic mechanisms underlying these processes. The basic brain mechanisms investigatd in the experimental hyperaminoacidemias listed above will include (a) polyribosomal stability in vivo, (b) initiation of protein synthesis and binding of messenger RNA to ribosomes in vitro, and (c) ribosomal protein phosphorylation. In addition, since alterations in lysosomal structure and function in the brain in experimental hyperaminoacidemia have been observed in this laboratory, the possible relationship of these alterations to variations in brain protein metabolism under thse conditions will also be explored. It is anticipated that these investigations may help to elucidate the mechanisms involved in the production of metabolic abnormalities which contribute to brain dysfunction in human aminoacidopathies.